Alkyl phenols have a broad range of medicinal properties ranging from central nervous system (CNS) effects to antioxidant activities. The effects of alkyl phenols on the CNS are generally sedative in nature.
2,6-Dialkylphenols having isopropyl and sec-butyl substituents are potent anesthetic/sedative compounds. For example, the dialkylphenol, propofol (2,6-diisopropylphenol) is used as an anesthetic agent in both humans and animals. This compound also serves as a muscle relaxant, anti-epileptic, anti-emetic, anti-spasmotic and as a bronchodilator. Propofol is sufficiently effective as an anticonvulsant that it is recommended for the acute treatment of status epilepticus in humans. The anticonvulsant effects of propofol and of the related compound, 2,6-di-secbutylphenol, have been confirmed in animal seizure models. 2,6-Di-sec-butylphenol (R,R) is currently undergoing development as an anesthetic due to its anesthetic potency and low cardiovascular side effects.
It was previously demonstrated that the addition of a 4-(1-hydroxy-2,2,2-trifluoroethyl) group (4-HTFE) to propofol (MB003) (FIG. 1) results in a compound that is also anticonvulsant. Anticonvulsant screening revealed that this 4-HTFE phenol is protective in the mouse 6 Hz (32 mA) model of partial epilepsy, whereas they have little to no protective effects in the mouse maximal electroshock (MES) and subcutaneous Metrazol (scMET) models. The 6 Hz model is considered an important animal model for therapy-resistant epilepsy. Therapy-resistant epilepsy is defined as cases of epilepsy that are not satisfactorily treated with available agents. This anticonvulsant profile, effectiveness in the 6 Hz model, but not in MES and scMET models, is similar to the profile of the successful anticonvulsant levetiracetam.
Propofol and 2,6-di-sec-butylphenol's potent sedative effects, properties considered toxic for anticonvulsant compounds, limit their usefulness in the more widespread treatment of seizures, and new compounds for use in therapy are needed.